Our studies in children and experimental animals show that low levels of blood lead inhibit activity of red cell pyrimidine 5' nucleotidase (E.C.3.1.3.5.; P5N; CMPase), an enzyme of the red cell that dephosphorylates the 5', 2' and 2 deoxymonophosphates of cytidine and uridine permitting their diffusion from the red cell. In rabbits, an oral intake of lead over six weeks time to a blood lead of 40-60 micrograms/dl results in the rapid accumulation of red cell pyrimidine nucleotides when the zinc erythrocyte protoporphyrins (ZEP) exceed 60 units. The temporal relationship and the log-log correlation of ZEP with pyrimidine nucleotides indicate that enzymatic depression in the reticulocyte is manifest in the mature cell and that pyrimidine nucleotide accumulation is a more stable index of chronic exposure than blood lead. This study investigates the red cell nucleotide profile of children and lead workers as related to other indices of exposure and evaluates a screening test for pyrimidine nucleotide accumulation. Animal studies are designed to test the hypothesis that the increase in red cell pyrimidine nucleotides may reflect a threshold for derangement of RNA synthesis and degradation in addition to alterations of pyrimidine metabolism.